We use entangled multimode coherent states to produce entangled giant graviton states, in the context of gauge/gravity duality. We make a smeared distribution of the entangled multimode coherent ...states on the circle, or on the five-sphere, in the higher dimensional view. In gauge/gravity duality, we analyze the superposition of giant graviton states, and the entangled pairs of giant graviton states. We map a class of angular distribution functions to unitary operations on the pairs. We also use Young tableau states to construct cat states and qudit states. Various bipartite quantum states involving Young tableau states are analyzed, including micro-macro entangled states. Mixed states of Young tableau states are generated, by using ensemble mixing using angular distribution functions, and also by going through noisy quantum channels. We then produce mixed entangled pair of giant graviton states, by including interaction with the environment and using noisy quantum channels.
CRISPR-Cas9 systems are bacterial adaptive immune systems that defend against infection by phages. Through the RNA-guided endonuclease activity of Cas9 they degrade double-stranded DNA with a ...protospacer adjacent motif (PAM) and sequences complementary to the guide RNA. Recently, two anti-CRISPR proteins (AcrIIA2 and AcrIIA4 from Listeria monocytogenes prophages) were identified, both of which inhibit Streptococcus pyogenes Cas9 (SpyCas9) and L. monocytogenes Cas9 activity in bacteria and human cells. However, the mechanism of AcrIIA2- or AcrIIA4-mediated Cas9 inhibition remains unknown. Here we report a crystal structure of SpyCas9 in complex with a single-guide RNA (sgRNA) and AcrIIA4. Our data show that AcrIIA2 and AcrIIA4 interact with SpyCas9 in a sgRNA-dependent manner. The structure reveals that AcrIIA4 inhibits SpyCas9 activity by structurally mimicking the PAM to occupy the PAM-interacting site in the PAM-interacting domain, thereby blocking recognition of double-stranded DNA substrates by SpyCas9. AcrIIA4 further inhibits the endonuclease activity of SpyCas9 by shielding its RuvC active site. Structural comparison reveals that formation of the AcrIIA4-binding site of SpyCas9 is induced by sgRNA binding. Our study reveals the mechanism of SpyCas9 inhibition by AcrIIA4, providing a structural basis for developing 'off-switch' tools for SpyCas9 to avoid unwanted genome edits within cells and tissues.
To characterize the clinical severity of covid-19 associated with the alpha, delta, and omicron SARS-CoV-2 variants among adults admitted to hospital and to compare the effectiveness of mRNA vaccines ...to prevent hospital admissions related to each variant.
Case-control study.
21 hospitals across the United States.
11 690 adults (≥18 years) admitted to hospital: 5728 with covid-19 (cases) and 5962 without covid-19 (controls). Patients were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and, if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: alpha (11 March to 3 July 2021), delta (4 July to 25 December 2021), and omicron (26 December 2021 to 14 January 2022).
Vaccine effectiveness calculated using a test negative design for mRNA vaccines to prevent covid-19 related hospital admissions by each variant (alpha, delta, omicron). Among patients admitted to hospital with covid-19, disease severity on the World Health Organization's clinical progression scale was compared among variants using proportional odds regression.
Effectiveness of the mRNA vaccines to prevent covid-19 associated hospital admissions was 85% (95% confidence interval 82% to 88%) for two vaccine doses against the alpha variant, 85% (83% to 87%) for two doses against the delta variant, 94% (92% to 95%) for three doses against the delta variant, 65% (51% to 75%) for two doses against the omicron variant; and 86% (77% to 91%) for three doses against the omicron variant. In-hospital mortality was 7.6% (81/1060) for alpha, 12.2% (461/3788) for delta, and 7.1% (40/565) for omicron. Among unvaccinated patients with covid-19 admitted to hospital, severity on the WHO clinical progression scale was higher for the delta versus alpha variant (adjusted proportional odds ratio 1.28, 95% confidence interval 1.11 to 1.46), and lower for the omicron versus delta variant (0.61, 0.49 to 0.77). Compared with unvaccinated patients, severity was lower for vaccinated patients for each variant, including alpha (adjusted proportional odds ratio 0.33, 0.23 to 0.49), delta (0.44, 0.37 to 0.51), and omicron (0.61, 0.44 to 0.85).
mRNA vaccines were found to be highly effective in preventing covid-19 associated hospital admissions related to the alpha, delta, and omicron variants, but three vaccine doses were required to achieve protection against omicron similar to the protection that two doses provided against the delta and alpha variants. Among adults admitted to hospital with covid-19, the omicron variant was associated with less severe disease than the delta variant but still resulted in substantial morbidity and mortality. Vaccinated patients admitted to hospital with covid-19 had significantly lower disease severity than unvaccinated patients for all the variants.
A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower ...disease severity than unvaccinated people.
To evaluate the association between vaccination with mRNA COVID-19 vaccines-mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)-and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease.
A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021.
COVID-19 vaccination.
Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression.
Among 4513 patients (median age, 59 years IQR, 45-69; 2202 48.8% women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) (P < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58).
Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.
Abstract
Periodontal disease can lead to severe degeneration of periodontium tissue and the global prevalence is continuously increasing with the growth and aging of population. Guided tissue ...regeneration (GTR) therapy with an occlusive membrane represents a golden standard in the dental clinic. Given the complex anatomy of the natural periodontium comprising alveolar bone, periodontal ligament (PDL) and cementum, GTR membrane/scaffolds with advanced multiphasic design are put forward to potentially repair the entire periodontium and restore its normal function. In principle, the multiphasic GTR membranes/scaffolds aim to coordinate the responses of both hard and soft tissues during the defect‐healing process, augment multi‐tissue regeneration, and optimize the formation of new periodontal attachment. In the past few decades, a diversity of GTR membranes/scaffolds with biphasic, triphasic, or gradient structures have been developed and demonstrated a substantial success in periodontal regeneration. This review covers the recent advancements in design of multiphasic GTR membranes/scaffolds from the aspects of materials, functional agents, and fabrication procedures, as well as their therapeutic efficacy assessed in vitro and in vivo. Finally, the limitations in current GTR therapy are discussed and future directions on the material design are also included accordingly.
The introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into the U.S. childhood immunization schedule in 2000 has substantially reduced the incidence of vaccine-serotype invasive ...pneumococcal disease in young children and in unvaccinated older children and adults. By 2004, hospitalizations associated with pneumonia from any cause had also declined markedly among young children. Because of concerns about increases in disease caused by nonvaccine serotypes, we wanted to determine whether the reduction in pneumonia-related hospitalizations among young children had been sustained through 2009 and whether such hospitalizations in older age groups had also declined.
We estimated annual rates of hospitalization for pneumonia from any cause using the Nationwide Inpatient Sample database. The reason for hospitalization was classified as pneumonia if pneumonia was the first listed diagnosis or if it was listed after a first diagnosis of sepsis, meningitis, or empyema. Average annual rates of pneumonia-related hospitalizations from 1997 through 1999 (before the introduction of PCV7) and from 2007 through 2009 (well after its introduction) were used to estimate annual declines in hospitalizations due to pneumonia.
The annual rate of hospitalization for pneumonia among children younger than 2 years of age declined by 551.1 per 100,000 children (95% confidence interval CI, 445.1 to 657.1), which translates to 47,000 fewer hospitalizations annually than expected on the basis of the rates before PCV7 was introduced. The rate for adults 85 years of age or older declined by 1300.8 per 100,000 (95% CI, 984.0 to 1617.6), which translates to 73,000 fewer hospitalizations annually. For the three age groups of 18 to 39 years, 65 to 74 years, and 75 to 84 years, the annual rate of hospitalization for pneumonia declined by 8.4 per 100,000 (95% CI, 0.6 to 16.2), 85.3 per 100,000 (95% CI, 7.0 to 163.6), and 359.8 per 100,000 (95% CI, 199.6 to 520.0), respectively. Overall, we estimated an age-adjusted annual reduction of 54.8 per 100,000 (95% CI, 41.0 to 68.5), or 168,000 fewer hospitalizations for pneumonia annually.
Declines in hospitalizations for childhood pneumonia were sustained during the decade after the introduction of PCV7. Substantial reductions in hospitalizations for pneumonia among adults were also observed. (Funded by the Centers for Disease Control and Prevention.).
A molecular arms race is progressively being unveiled between prokaryotes and viruses. Prokaryotes utilize CRISPR-mediated adaptive immune systems to kill the invading phages and mobile genetic ...elements, and in turn, the viruses evolve diverse anti-CRISPR proteins to fight back. The structures of several anti-CRISPR proteins have now been reported, and here we discuss their structural features, with a particular emphasis on topology, to discover their similarities and differences. We summarize the CRISPR-Cas inhibition mechanisms of these anti-CRISPR proteins in their structural context. Considering anti-CRISPRs in this way will provide important clues for studying their origin and evolution.
Matching area selection is a key problem of the gravity matching navigation method, especially for underwater application. The gravitational profile varies when the vehicle gets into the matching ...area in different directions. Therefore, the matching navigation efficiency is also distinct due to the directionality of matching area. In this study, based on the fractal geometry theory, a characteristic parameter-isotropic coefficient, which can measure the directionality of gravity matching area-is proposed by analyzing the spectrum character of gravity anomaly sequence on 3-D surface. Instead of single parameter, the comprehensive characteristic parameter is built by combining traditional gravity parameters and isotropic coefficient through an analytic hierarchy process for matching area selection. Compared with the traditional method, simulation results prove that the matching area selected by the improved comprehensive characteristic parameter method not only has larger coverage, but also has better directivity.
The inpatient and outpatient burden of human metapneumovirus (HMPV) infection among young children has not been well established.
We conducted prospective, population-based surveillance for acute ...respiratory illness or fever among inpatient and outpatient children less than 5 years of age in three U.S. counties from 2003 through 2009. Clinical and demographic data were obtained from parents and medical records, HMPV was detected by means of a reverse-transcriptase polymerase-chain-reaction assay, and population-based rates of hospitalization and estimated rates of outpatient visits associated with HMPV infection were determined.
HMPV was detected in 200 of 3490 hospitalized children (6%), 222 of 3257 children in outpatient clinics (7%), 224 of 3001 children in the emergency department (7%), and 10 of 770 asymptomatic controls (1%). Overall annual rates of hospitalization associated with HMPV infection were 1 per 1000 children less than 5 years of age, 3 per 1000 infants less than 6 months of age, and 2 per 1000 children 6 to 11 months of age. Children hospitalized with HMPV infection, as compared with those hospitalized without HMPV infection, were older and more likely to receive a diagnosis of pneumonia or asthma, to require supplemental oxygen, and to have a longer stay in the intensive care unit. The estimated annual burden of outpatient visits associated with HMPV infection was 55 clinic visits and 13 emergency department visits per 1000 children. The majority of HMPV-positive inpatient and outpatient children had no underlying medical conditions, although premature birth and asthma were more frequent among hospitalized children with HMPV infection than among those without HMPV infection.
HMPV infection is associated with a substantial burden of hospitalizations and outpatient visits among children throughout the first 5 years of life, especially during the first year. Most children with HMPV infection were previously healthy. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health.).
Astrocytes respond to and regulate neuronal activity, yet their role in mammalian behavior remains incompletely understood. Especially unclear is whether, and if so how, astrocyte activity regulates ...contextual fear memory, the dysregulation of which leads to pathological fear-related disorders. We generated
GFAP-ChR2-EYFP
rats to allow the specific activation of astrocytes in vivo by optogenetics. We found that after memory acquisition within a temporal window, astrocyte activation disrupted memory consolidation and persistently decreased contextual but not cued fear memory accompanied by reduced fear-related anxiety behavior. In vivo microdialysis experiments showed astrocyte photoactivation increased extracellular ATP and adenosine concentrations. Intracerebral blockade of adenosine A
1
receptors (A
1
Rs) reversed the attenuation of fear memory. Furthermore, intracerebral or intraperitoneal injection of A
1
R agonist mimicked the effects of astrocyte activation. Therefore, our findings provide a deeper understanding of the astrocyte-mediated regulation of fear memory and suggest a new and important therapeutic strategy against pathological fear-related disorders.
Memory is the record of what we learn over time and is essential to our survival. But not all memories are helpful. Repeatedly recalling a traumatic event – such as an assault – can be harmful. About 1 in 3 people who experience severe trauma go on to develop post-traumatic stress disorder (PTSD), in which they re-live the traumatic event in the form of flashbacks and nightmares. Others develop panic disorder, phobias or depression.
Preventing this chain of events is challenging because fear memories form rapidly and last a long time. Current treatments involve re-exposing individuals to the traumatic event. This could be real-life exposure in the case of a phobia. Or it could involve visualizing the event, in the case of PTSD. Controlled re-exposure can help individuals learn new coping strategies. But it does not erase the initial fear memory.
A better approach might be to take advantage of the fact that new memories are unstable. To form a long-lasting memory trace, newly acquired information must go through a process called consolidation to stabilize it. This process takes place in an area of the brain called the hippocampus. If consolidation does not occur, new memory traces can fade away.
Li, Li et al. now show that preventing consolidation in the rat brain stops the animals from forming lasting memories of a stressful event, namely a foot shock. In the study, the rats first learned to associate a foot shock with a tone. This training took place inside a specific chamber. After learning the association, the rats began to freeze – a sign of fear – whenever they entered the chamber. This happened even if the tone was not played. But Li, Li et al. showed that they could reduce this fear response by activating cells in the hippocampus known as astrocytes, shortly after the learning episode.
Activating the astrocytes made them release a substance called adenosine. Molecules of adenosine then bound to and activated proteins called adenosine A
1
receptors. Administering a drug that activated these receptors directly had the same effect as activating the astrocytes themselves. This suggests that drugs of this type could one day help patients with fear-related disorders such as PTSD and phobias. For this to become a reality, new studies must test different drugs and find the best ways of administering them. After testing in animal models, the next step will be preliminary clinical trials in people.
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